Disease relevance of SERPINE2

• We found that PN-1 expression was elevated over that found in normal mammary tissue; an increase of 1.5- to 3.5-fold in 21 of 26 human breast tumors examined [1].
• The SERPINE2 gene and chronic obstructive pulmonary disease [2].
• Association of five of these SNPs with COPD was replicated in a case-control analysis, with cases from the National Emphysema Treatment Trial and controls from the Normative Aging Study. Family-based and case-control haplotype analyses supported similar regions of association within the SERPINE2 gene [3].
• SERPINE2 expression was weak or absent in all normal pancreas and chronic pancreatitis tissue samples examined [4].
• One of the genes most strongly overrepresented in the highly metastatic subclone S2-007 as compared with the rarely metastatic subclone S2-028 was the serine proteinase inhibitor SERPINE2 (protease nexin I), suggesting that this protein may play an important part in the process of metastasis [4].

Psychiatry related information on SERPINE2

• Protease nexin I immunostaining in Alzheimer's disease [5].
• Thoughts about psychological factors, PNI, and cancer [6].

High impact information on SERPINE2

• Their cilia showed an eccentric central pair of tubules but otherwise had a normal central sheath, outer-doublet microtubules, nexin links and dynein arms [7].
• Recently, we showed that heparin virtually blocked the binding of thrombin-protease nexin complexes to both mouse and human cells without affecting the ability of these cells to respond to thrombin [8].
• Western analysis showed that scleroderma fibroblasts also secreted more PN1 [9].
• PN1 mutagenized at its active site and antisense PN1 both failed to increase collagen promoter activity [9].
• These results suggest that overexpression of enzymatically active PN1 may play a pathogenic role in the development of the scleroderma phenotype [9].

Chemical compound and disease context of SERPINE2

• Serpin inhibitors of urokinase and thrombin in normal rat brain and the 9L brain tumor: evidence for elevated expression of protease nexin I-like inhibitor and a novel sodium dodecyl sulfate-activated tumor antithrombin [10].
• These results indicate, that in C6 glioma cells, PN-1 secretion could be regulated by both Go1alpha expression and activation [11].
• Moreover, we examined in vivo vascular expression of PN-1 in a model of chronic hypertension induced by long-term administration of N(G)-nitro-L-arginine methyl ester (L-NAME) [12].

Biological context of SERPINE2

• Based on this observation, we investigated if PN-1 is also expressed in human breast cancers where it may contribute to the regulation of uPA and participate in the development of a metastatic phenotype [1].
• Binding of PN-1 to immobilized collagen type IV was demonstrated using an enzyme-linked immunosorbent assay; the concentration of PN-1 necessary to obtain 50% saturation of the immobilized collagen type IV binding sites was approximately 15 nM [13].
• Structural and mutational analyses of the molecular interactions between the catalytic domain of factor XIa and the Kunitz protease inhibitor domain of protease nexin 2 [14].
• Protease nexin 1 (PN1) in solution forms inhibitory complexes with thrombin or urokinase, which have opposing effects on the blood coagulation cascade [15].
• Because PN1 used in previous studies was purified over a monoclonal antibody column, we propose that the allosteric regulation of PN1 target protease specificity by collagen type IV is a result of the purification protocol [15].

Anatomical context of SERPINE2

• Moreover, cancer cells in invasive SERPINE2-expressing tumors tended to adopt a spindle-shaped morphology and strongly expressed the mesenchymal intermediate filament marker vimentin [4].
• It is shown that protease nexin is actually synthesized by fibroblasts and represents about 1% of their secreted protein [16].
• Pericytes (in contrast to endothelial cells and astrocytes) were found to be the principal in vitro source of the serpin protease nexin-1 (PN-1), known to have primarily antithrombin effects [17].
• PNI is highly expressed and developmentally regulated in the nervous system where it is concentrated at neuromuscular junctions and also central synapses in the hippocampus and striatum [18].
• Southern blot hybridization of PNI cDNA to somatic cell hybrids placed the structural gene for PNI (locus PI7) on human chromosome 2q33-q35 and to syntenic chromosomes in the mouse (chromosome 1) and sheep (chromosome 2) [18].

Associations of SERPINE2 with chemical compounds

• In the presence of heparin, protease nexin inhibits thrombin at a nearly diffusion-controlled rate [16].
• Protease nexin-1 (PN-1) is a member of the serpin superfamily of serine protease inhibitors which can rapidly inhibit thrombin, urokinase, and plasmin [13].
• Previous work showed that heparan sulfate proteoglycan is largely responsible for the acceleration of thrombin inhibition by PN-1 [13].
• Protease nexin contains approximately 6% carbohydrate, with 2.3% amino sugar, 1.1% neutral sugar, and 3.0% sialic acid [16].
• Follicles collected from the abattoir were classified as non-atretic, early-atretic or atretic based on FF estradiol and progesterone content: PN-1 protein levels in FF were significantly higher in non-atretic than in atretic follicles, and plasmin activity was correspondingly higher in the atretic follicles [19].

Physical interactions of SERPINE2

• The efficient catabolism of thrombin-protease nexin 1 complexes is a synergistic mechanism that requires both the LDL receptor-related protein and cell surface heparins [20].
• These results indicate that active thrombin binds covalently to a specific endothelial protein that is in several respects similar to fibroblast or platelet protease nexin and provides a thrombin binding site distinct from thrombomodulin and glycosaminoglycans [21].
• Addition of thrombin-antithrombin III complexes to the supernatant solution of activated platelets also led to complexes with thrombospondin, demonstrating that serpins other than platelet protease nexin facilitate incorporation of thrombin into complexes with thrombospondin [22].

Regulatory relationships of SERPINE2

• The relatively high value of kass. for protease nexin I (5 x 10(3) M-1.s-1) suggested that it may be involved in the control of activated protein C on the surface of platelets where protein nexin I is present at relatively high concentrations [23].
• Purified protease nexin inhibits purified HF cell urokinase action on both plasminogen and low molecular weight substrates [24].
• While antithrombin was fully active against acrosin, more than one molecule of Arg-alpha 1-antitrypsin and protease nexin 1 was required to inhibit one molecule of acrosin [25].

Other interactions of SERPINE2

• CONCLUSION: Elevated levels of GDN/PN1 and XIP mRNAs induced by Allitridi provide valuable molecular evidence for elucidating the garlic's efficacies against neurodegenerative and inflammatory diseases [26].
• A quantile box plot of these data demonstrates that the elevated PN-1 expression in breast tumor tissues directly correlates with the increased expression levels found for PAI-1 and uPA [1].
• Protease nexin 1 is a potent urinary plasminogen activator inhibitor in the presence of collagen type IV [15].
• Analysis of the amino acid composition of purified protease nexin indicates that it is evolutionarily related to antithrombin III and heparin cofactor II [16].
• The present paper describes chemical and functional properties of protease nexin, a serine protease inhibitor released from cultured human fibroblasts [16].

Analytical, diagnostic and therapeutic context of SERPINE2

• RESULTS : Using quantitative real-time PCR analysis, we measured PN-1 mRNA expression in tissues obtained from 26 human breast tumor biopsies and compared these values with those obtained from 10 normal breast tissue samples [1].
• After the integration of murine and human microarray data to inform candidate-gene selection, we observed significant family-based association and independent replication of association in a case-control study, suggesting that SERPINE2 is a COPD-susceptibility gene and is likely influenced by gene-by-smoking interaction [3].
• We propose that SERPINE2 overexpression enhances the invasive potential of pancreatic cancer cells in nude mouse xenografts by altering ECM production and organization within the tumors [4].
• Northern blot verification showed that lesional and nonlesional scleroderma fibroblasts had three- to five-fold increased levels of PN1 mRNA compared with healthy fibroblasts [9].
• In situ hybridization of skin biopsy specimens demonstrated PN1 expression in the dermis of four out of six scleroderma patients but no PN1 expression in the dermis of six healthy volunteers [9].

References